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Global Trends in Anaphylaxis Epidemiology and Clinical Implications
Journal Pre-proof Global Trends in Anaphylaxis Epidemiology and Clinical Implications Paul J. Turner, FRACP PhD, Dianne E. Campbell, FRACP PhD, Megan S. Motosue, MD, Ronna L. Campbell, M.D., Ph.D. PII:
S2213-2198(19)30967-5
DOI:
https://doi.org/10.1016/j.jaip.2019.11.027
Reference:
JAIP 2571
To appear in:
The Journal of Allergy and Clinical Immunology: In Practice
Received Date: 4 October 2019 Revised Date:
18 November 2019
Accepted Date: 18 November 2019
Please cite this article as: Turner PJ, Campbell DE, Motosue MS, Campbell RL, Global Trends in Anaphylaxis Epidemiology and Clinical Implications, The Journal of Allergy and Clinical Immunology: In Practice (2019), doi: https://doi.org/10.1016/j.jaip.2019.11.027. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
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Global Trends in Anaphylaxis Epidemiology and Clinical Implications
2 3
Paul J Turner FRACP PhD,1,2 Dianne E Campbell FRACP PhD,2,3 Megan S. Motosue, MD,4 Ronna L.
4
Campbell, M.D., Ph.D.5
5 6
1Section
of Inflammation, Repair & Development, National Heart & Lung Institute, Imperial College
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London, London, United Kingdom; 2Discipline of Child and Adolescent Health, University of Sydney,
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Sydney, Australia; 3Department of Allergy and Immunology, Children’s Hospital at Westmead,
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Sydney, Australia; 4Department of Allergy and Immunology, University of Hawaii, John A. Burns
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School of Medicine, Honolulu, Hawaii, United States; 5Department of Emergency Medicine, Mayo
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Clinic College of Medicine and Science, Rochester, MN, United States
12 13
Corresponding author:
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Ronna L. Campbell, MD, PhD
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Department of Emergency Medicine, Mayo Clinic College of Medicine and Science
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200 First St SW, Rochester, MN 55905
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Tel: (507) 255-7002
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Fax: 507-255-6592
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Email: [email protected]
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Author declaration: All authors have revised and approved the final version of the manuscript for
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submission. This work is original and hasn’t been published nor is under consideration for
23
publication elsewhere.
2 24
Conflicts of interest: R.L. Campbell has received consulting fees from EB Medicine and is an author
25
for UpToDate. P.J. Turner reports grants from the UK Medical Research Council and National
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Institute for Health Research (NIHR) Policy Research Programme; and received consultancy and
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lecture fees from Aimmune Therapeutics, Allergenis and DBV Technologies. D.E Campbell receives
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part time salary from DBV-technologies and reports grants from The National Health and Medical
29
Research Council of Australia (NHMRC), and received advisory board fees from Allergenis. M.S.
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Motosue declares no conflicts of interest.
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Funding Some of the data analysis in this manuscript was funded through a UK Medical Research
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Council Clinician Scientist award to P.J. Turner (reference MR/K010468/1).
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Word count: 2889
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Abstract
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The true global scale of anaphylaxis remains elusive, because many episodes occur in the
37
community without presentation to healthcare facilities, and most regions have not yet developed
38
reliable systems with which to monitor severe allergic events. The most robust datasets currently
39
available are based largely on hospital admissions, which are limited by inherent issues of
40
misdiagnosis, misclassification and generalizability. Despite this, there is convincing evidence of a
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global increase in rates of all cause-anaphylaxis, driven largely by medication and food-related
42
anaphylaxis. There is no evidence of parallel increases in global all-cause anaphylaxis mortality,
43
with surprisingly similar estimates for case fatality rates at approximately 0.5-1% rate of fatal
44
outcomes for hospitalizations due to anaphylaxis across several regions.
45
Studying regional patterns of anaphylaxis to certain triggers have provided valuable insights into
46
susceptibility and sensitizing events: for example, the link between the monoclonal antibody
47
cetuximab and allergy to mammalian meat. Likewise, data from published fatality registers can
48
identify potentially modifiable risk factors which can be used to inform clinical practice, such as
49
prevention of delayed epinephrine administration, correct posturing during anaphylaxis, special
50
attention to populations at risk (such as the elderly on multiple medications) and use of venom
51
immunotherapy in individuals at risk of insect-related anaphylaxis.
4 52
Key words: Anaphylaxis, biphasic, epidemiology, time trends, food allergy.
5 53
Abbreviations
54
Ab, antibodies
55
CCL2, chemokine ligand-2
56
EAACI, European Academy of Allergy and Clinical Immunology
57
FAAN, Food Allergy and Anaphylaxis Network
58
ICD-11, International Classification of Disease, Eleventh Revision
59
ICU, Intensive Care Unit
60
LTP, Lipid Transfer Protein
61
NIAID, National Institute of Allergy and Infectious Diseases
62
UK, United Kingdom
63
USA, United States of America
64
WAO, World Allergy Organization
65
WHO, World Health Organization
66
α- gal, galactosyl-α-(1,3)-galactose
6 67
Introduction
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Anaphylaxis represents the more severe end of the spectrum of allergic reactions, and is most
69
commonly triggered by medication, food or insect stings. Measuring and evaluating
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epidemiological data related to episodes of anaphylaxis is an important means by which trends,
71
burden of disease and risk factors can be identified. Such information can highlight novel emerging
72
allergens, changes in epidemiology and risk-factor associations, which can in turn inform clinical
73
practice and may prevent future severe reactions and fatalities.
74
Difficulties in the collection and interpretation of epidemiological anaphylaxis data must be
75
acknowledged. These include variation in definitions of anaphylaxis across different regions of the
76
world, logistical and coding issues related to collection of large health service data sets and the
77
inherent difficulties in collecting data for a disease state which largely occurs in the community, not
78
within a hospital or health facility.
79 80
Trends in Anaphylaxis Epidemiology
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Hospital admissions datasets represent the largest and most robust data available to understand
82
trends in anaphylaxis; however, they probably underestimate the true rate of anaphylaxis, as this
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frequently occurs in the community or outside of hospital settings, and only the minority of cases
84
result in hospitalization.
85
Anaphylaxis accounts for up to 0.26% of overall hospital admissions(1). In general, the literature
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reports global (UK, Europe, USA, Australia, New Zealand) increases in hospitalizations for
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anaphylaxis – both with respect to all-cause anaphylaxis (Figure 1) and by trigger (Figures 2 &
88
3)(2-10); Taiwan appears to be an exception, where hospitalizations have not increased despite an
89
increase in hospital referrals for anaphylaxis(11). Data is available relating to hospital presentations
7 90
(rather than hospital admissions) from South Korea and New Zealand: all-cause anaphylaxis is
91
estimated to have increased 1.7-fold over the period 2010-2014 in South Korea(12), most markedly
92
in young children, while there has been a 2.8 fold increase in food-related anaphylaxis admissions
93
in children in New Zealand between 2006-2015(13).
94
There are significant differences in global anaphylaxis admission rates, with the highest rates in
95
Australia and lower rates reported in Spain, Taiwan and USA. This may be due, in part, to different
96
thresholds for observation in hospital following a reaction, and whether this occurs in an
97
“observation unit,” which may or may not be coded as a hospital admission. Less than 20% of
98
emergency presentations with anaphylaxis are admitted (either to an observation unit or to
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hospital ward) in the USA(6), which could explain (at least in part) the lower rate of hospitalization
100
in the USA (similarly, in Spain, most patients are discharged without hospitalization). This is in
101
contrast to countries such as the UK where national guidelines recommend hospitalization for
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anaphylaxis, particularly in children at first presentation(14). In general, the increase in
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hospitalizations is predominantly due to food-related anaphylaxis, particularly in children(3, 4, 7, 8,
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10, 15-19), although data are limited for non-food allergens (Figure 32B). Interestingly, rates of
105
hospitalization are roughly equivalent in most regions (although highest in Australia), which
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implies that perhaps the threshold for in-patient observation is not particularly different between
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countries.
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Despite this increase, there is little evidence that the overall rate of fatal outcomes has increased(8,
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10, 20-23), with the mortality rate declining in many regions. Furthermore, mortality seems similar
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in those regions where data is available, at around 0.5-1 fatality per million (population). The
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notable exception is Australia, where all-cause fatal anaphylaxis rates increased by 6.2% per annum
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from 1997 to 2013, predominantly due to food triggers(8). However, when these data are analyzed
8 113
by case fatality rate (proportion of cases admitted to hospital which result in a fatal outcome),
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mortality has fallen, including with respect to food-related fatal anaphylaxis in Australia (Figure 4).
115 116
Trigger specific epidemiology
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Food represents the most common trigger for anaphylaxis admissions to hospital, but not the most
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common cause of anaphylaxis-related fatalities. Hospitalizations due to food-related anaphylaxis
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peak in the pediatric age range, but contribute significantly to adult admissions, where typically
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anaphylaxis admissions due to medication exceed those due to food by the 6th decade onwards.
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Mortality from food-related anaphylaxis is consistently lower than other causes across all regions.
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This is in agreement with the observation that while food-induced anaphylaxis is relatively
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common, fatal outcomes are rare, with a reported incidence of 1.35–2.71 per million person-
124
years(24). Curiously, the USA appears to have a lower mortality rate for food-related anaphylaxis
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(but not the proportion of hospital admissions resulting in fatal outcome i.e. case fatality rate)
126
compared to other regions, despite a higher mortality from all-cause anaphylaxis (both in terms of
127
deaths per unit population and case fatality rate) compared to Canada and UK. The reasons for this
128
are unclear, but may be due to miscoding: Ma et al reported that 75% anaphylaxis fatalities
129
recorded between 1999 and 2009 in the USA were coded as “trigger unspecified”(4).
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Both the USA and Australia have reported significant increases in fatality rates due to drug-induced
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anaphylaxis(8, 20) (Figure 3B), which may represent an increasing tendency towards
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polypharmacy in an ageing population – although there is no evidence that this has affected the
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case fatality rate (Figure 4). Analysis of data from a national adverse drug reporting system in
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Vietnam over the period 2010-2016 found a significant increase in the rate of drug related
135
anaphylaxis, predominantly attributed to antibiotics(25). McCall et al recently analyzed time
136
trends in USA anaphylaxis-related hospitalizations in pregnant women between 2004 and 2014, to
9 137
assess whether drug-related anaphylaxis had increased as a result of an increase in deliveries by
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cesarean section; reassuringly, the authors did not identify such an increase in this specific patient
139
cohort(26).
140
Insect related anaphylaxis rates appear to have remained relatively stable (or decreasing) over
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many years, in comparison to medication and food. Although they represent a small proportion of
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hospital anaphylaxis admissions, they are relatively over-represented in fatalities, underlying the
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seriousness of insect allergy. Potentially modifiable factors highlighted by anaphylaxis registries
144
include delayed treatment due to rural location of incident, lack of preparedness for anaphylaxis
145
and lack of prior immunotherapy for venom allergy(8).
146 147
Novel and emerging allergens
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Lipid Transfer Protein (LTP)-associated food anaphylaxis is reported to be the most common cause
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of food anaphylaxis in adults in the Mediterranean region(27), with a north-to-south regional
150
gradient in prevalence(28). It is also the most common trigger for exercise-associated, food-related
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anaphylaxis in this region(29). The epidemiology of this syndrome elsewhere is unclear: although
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sporadic case reports of LTP-associated food anaphylaxis occur globally, it remains unclear exactly
153
why this appears to be a largely Mediterranean phenomena, and whether rates are truly
154
increasing(30).
155
Allergy and anaphylaxis to the oligosaccharide galactosyl-α-(1,3)-galactose (α-gal) is an emerging
156
cause of anaphylaxis in tick-endemic regions globally. It was the regional USA epidemiology of
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anaphylaxis to cetuximab – concentrated in the southeastern USA states of Tennessee, Arkansas
158
and South Carolina with few anaphylaxis cases reported in Massachusetts and northern California –
159
which led to the understanding that this form of anaphylaxis was related to prior sensitization to α-
10 160
gal via tick bites(31). In the form of non-primate mammalian meat anaphylaxis, symptoms present
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with an “atypical” delay in onset from exposure to anaphylaxis - typically 3-6 hours following
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mammalian meat ingestion(32, 33) (although reactions up to 10 hours after exposure have been
163
reported). Cases have been reported in most regions, including Australia(34), Japan(35), USA(30),
164
South America, Africa(36) and Europe, but it is unclear if rates are increasing, with many historical
165
cases likely to have been unrecognized and undiagnosed(37).
166
Monoclonal antibodies (mAb) are exponentially used in clinical practice to treat a wide range of
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diseases, and represent a novel therapeutic class that is increasingly associated with anaphylaxis, as
168
recently reviewed(38). Ironically, the agent most commonly reported to trigger anaphylaxis is the
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anti-IgE mAb omalizumab(38), however systematic reporting and analysis of co-factors related to
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mAb-related anaphylaxis (aside from cetuximab) are currently lacking.
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Biphasic Anaphylaxis
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Studies assessing the frequency of biphasic anaphylaxis have been undertaken worldwide(39). The
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true incidence of biphasic anaphylaxis remains unclear, hindered by the use of differing definitions
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of biphasic anaphylaxis. Studies evaluating the incidence of biphasic reactions have reported rates
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ranging from almost 20%(40) to less than 1%(41). A meta-analysis of 27 studies, which included
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4114 patients with anaphylaxis and 192 biphasic reactions, reported a biphasic reaction rate of
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4.6% and a median time of onset of 11 (range 0.2–72) hours(39). Risk factors associated with the
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development of a biphasic reaction have been difficult to identify. However, the data suggest that
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increased severity of the initial reaction, (42, 43), a wide pulse pressure(39, 44) at presentation,
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increased requirement for epinephrine to treat the initial reaction(44-47), and delayed
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administration of epinephrine (44, 45, 48)may increase the risk. Two systematic reviews(49, 50)
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failed to find evidence that corticosteroids reduce the risk of a biphasic reaction. Although, no fatal
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reactions have been reported in contemporary studies evaluating biphasic anaphylaxis,
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approximately 20-55% of biphasic reactions are treated with epinephrine (40, 44, 46, 48, 51). In
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addition, ICU admission may be required in 4-14% of patients (51, 52).
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Collecting and interpreting anaphylaxis data - pitfalls and limitations
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In order to effectively understand and learn from anaphylaxis data, it is important to understand
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the potential biases that can confound any inferences made. Selection bias occurs when
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anaphylaxis cases in any given dataset differ systematically from general anaphylaxis, resulting in
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systematic differences which can impact interpretation. For example, there are a number of
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different datasets which can be used to monitor epidemiological trends, ranging from emergency
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department presentations to public datasets, health insurance databases and anaphylaxis registries.
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These datasets may only capture cases presenting to specific healthcare facilities and not
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anaphylaxis in the community, which often does not present to healthcare professionals. Insurance
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databases may only include cases in insured individuals or those who present to specific facilities,
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and are therefore unlikely to represent all socioeconomic groups. Anaphylaxis registries are, by
199
nature, retrospective and subject to reporting and recall bias, although one state in Australia now
200
has mandatory anaphylaxis reporting of any case presenting to a hospital facility (but not to
201
healthcare professionals outside hospital)(53).
202
Selection bias becomes a major confounder when evaluating severity: mild reactions may not be
203
included due to non-presentation to healthcare facilities, while severe (fatal) cases may occur pre-
204
hospital and not be registered, or misclassified as being due to a different cause of death. There is
205
little consensus as to what constitutes severe reactions: in a large prospective cohort of anaphylaxis
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presenting to an emergency department, 31% of cases had wheeze without any other major organ
207
features (54). Such presentations might be coded as asthma rather than anaphylaxis. In contrast,
12 208
non-anaphylaxis reactions that involve significant generalized urticaria and facial angioedema
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alone might be miscoded as anaphylaxis due to ‘visual’ severity. A further concern, particularly with
210
respect to drug-induced anaphylaxis, is under-recognition and under-reporting potentially due to
211
medicolegal concerns: many such cases result from patients being administered medication to
212
which they were already known to be allergic(8, 55).
213
The other important bias to consider is information bias, which relates to misclassification of data.
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At a broad level, large datasets depend on medical coding, which are prone to misclassification(24,
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56). This issue is further confounded by differences in the definition of anaphylaxis(14), and the
216
extent to which any definition is used to determine the coding, as recently highlighted by Wang et
217
al(57). It is not uncommon, particular in the emergency setting, for mild allergic reactions to be
218
coded as anaphylaxis, and vice versa(58,59). For example, 48% of anaphylactic reactions in an
219
emergency department in New York State were not coded as anaphylaxis despite fulfilling
220
diagnostic criteria (59). It is also possible that non-allergic anaphylaxis mimics such as chronic
221
idiopathic urticaria and hereditary angioedema could be misclassified as anaphylaxis. This can
222
impact interpretation, for example the inclusion of more mild cases as anaphylaxis will skew the
223
result of any intervention towards a more favorable outcomes (potential channeling bias).
224
Identifying specific anaphylaxis triggers is important, however this information is frequently not
225
collected with existing coding systems. Many coded anaphylaxis reactions are labelled “trigger
226
unspecified”, which hampers the evaluation of risk factors for severe reactions and in assessing
227
trends for specific triggers. For example, in an analysis of USA data between 1999 and 2009, over
228
two thirds of cases – hospitalizations and fatalities – were classified as “unspecified trigger”(4). The
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new ICD-11 coding(60) should improve this, although there may be initial difficulties in monitoring
230
historical trends if different coding systems have to be integrated for analysis.
13 231
Caution is needed when interpreting mortality data: death certification is prone to miscoding (e.g.
232
cases of anaphylaxis may be miscoded as “severe asthma”)(61). Most death certification follows
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WHO guidelines, where one part gives the condition or sequence of conditions leading directly to
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death, a second section gives details of any associated conditions that contributed to the death, but
235
are not part of the causal sequence. There have been examples of this resulting in gross over-
236
estimates in terms of fatalities due to allergy, if death certificates include allergy diagnoses even
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when they are not factors which contributed to the fatal outcome.
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Monitoring the rate of hospital admissions is a frequent method used to assess epidemiology, but
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there are many factors which determine whether a particular patient is admitted to hospital or
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discharged. For example, guidance in the UK implemented in 2011 recommended that all children
241
with food-related allergic reactions be admitted to the hospital following presentation to the
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emergency department, which might have caused an artefactual increase in rates of
243
hospitalization(10). Using prescription data for epinephrine auto-injectors as a surrogate for
244
prevalence is also subject to similar external “modifiers”, since changes in prescription patterns
245
cannot solely be attributed to changes in prevalence.
246
Despite limitations, analyzing changes in anaphylaxis epidemiology over time is an important tool
247
for clinicians, researchers and those advocating for improvements in health policy to address the
248
burden of disease. The effect of bias can be mitigated in part by the use of the same methodology to
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compare trends in any given dataset – so although there may be issues relating to information bias,
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if these are constant over the time period under study in any given dataset, then underlying trends
251
are likely to be real even if the biases confound any comparison between different datasets.
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Lessons for Improvement in Diagnosis and Management
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Recognition of anaphylaxis can be difficult: this is confounded by differences in diagnostic criteria.
255
This is particularly true for food-induced anaphylaxis: according to the National Institute of Allergy
256
and Infectious Diseases/ Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria(62)
257
(subsequently adopted by the World Allergy Organization (WAO)(63)), a food-induced reaction
258
with hives and vomiting could be consistent with anaphylaxis, but such a reaction (i.e. skin and gut
259
symptoms) would not be considered as anaphylaxis in the UK(64) and Australia(65), in the
260
absence of respiratory or cardiovascular symptoms. Furthermore, isolated respiratory reactions in
261
the absence of skin or gut symptoms are not classified as anaphylaxis according to NIAID/FAAN
262
criteria, despite this being a common presentation for fatal food anaphylaxis (66,67). For example,
263
in the largest phase 3 study of oral immunotherapy performed to date (the PALISADE study), at
264
least one third of 551 participants received epinephrine during entry food challenge (68), but only
265
28 had reactions which met the NIAID/FAAN criteria for anaphylaxis (69). Interestingly, 35
266
subjects were treated for wheezing – 7 more than those diagnosed with anaphylaxis – and at least
267
14 without anaphylaxis received multiple doses of epinephrine (69). These differences not only
268
impact patient care practices, but also have implications for service evaluation and research by
269
confounding comparisons of reported incidence rates of anaphylaxis and epinephrine use due to
270
differences in definition. Increased collaboration to create an international consensus is needed, to
271
avoid these incongruities. The WAO Anaphylaxis Committee has recently proposed a refinement of
272
the NIAID/FAAN criteria and its rationale for doing so(70) (Table 1), to help achieve this important
273
goal. Similarly, the implementation of ICD-11 classification will also improve consistency of coding
274
and facilitate future evaluation of epidemiological trends.
275
While largely a clinical diagnosis, biomarkers and specifically serum tryptase may support
276
the diagnosis of anaphylaxis and aid in differentiating anaphylaxis from its mimics such as
277
idiopathic systemic capillary leak syndrome and severe asthma, although serum tryptase is also
278
elevated in fatal asthma(71). This can be important in the context of monitoring trends for more
15 279
severe reactions. Yet despite its recommendation in current guidelines(63, 72), the role of tryptase
280
in “real world” practice remains debated. From a practical standpoint, serum tryptase is not readily
281
available to emergency providers as it often takes several days for results to become available.
282
Moreover, while the positive predictive value of serum tryptase is high (93%), the negative
283
predictive value is low (17%) (73) and may not be helpful, particularly for food-induced
284
anaphylaxis when tryptase is frequently not elevated. Other biomarkers (such as platelet-activating
285
factor, cysteinyl leukotrienes, chemokine ligand-2 (CCL2)) have been proposed(74) but can be
286
difficult to measure even under laboratory conditions. Future studies may need to consider
287
examining the sensitivity and specificity of a combination of biomarkers.
288
With regards to anaphylaxis management , while epinephrine remains the first line
289
treatment, glucocorticoids and antihistamines including both H1- and H2-antihistamines are often
290
recommended as second-line treatment (although the latest European Academy of Allergy and
291
Clinical Immunology (EAACI) guidelines relegate antihistamines to a 3rd line measure to help
292
relieve cutaneous symptoms, due to concerns that their use might delay the appropriate further
293
administration of epinephrine or fluids during patient stabilization)(75). The benefit of
294
antihistamines and glucocorticoids in both acute management and prevention of biphasic reactions
295
has not been established, and there is increasing evidence that glucocorticoids may be harmful
296
rather than simply being of no benefit(76). What role, if any, glucocorticoids and antihistamines
297
should have in anaphylaxis management needs further clarification, potentially through
298
comparison of outcomes between different units/regions. Reports from regional fatal anaphylaxis
299
registries have suggested that modifiable risk factors for severe and fatal anaphylaxis appear to
300
include polypharmacy in the elderly, delayed administration of epinephrine, maintaining an upright
301
posture (with dependent lower body) during anaphylaxis, failure to recognized past history of
302
medication allergies and failure to undertake venom immunotherapy in at-risk venom-allergic
303
individuals (77).
16 304
Comprehensive management of patients who have had anaphylaxis can be complex, so
305
partnerships between allergy specialists, emergency medicine and primary care providers are
306
necessary. Exploring the use of new tools, including the use of electronic medical records in
307
providing structured ordered sets, discharge instructions and automatic allergy referral system,
308
may provide additional solutions to improve the diagnosis and management of anaphylaxis.
309
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27 543
Table 1: Amended criteria for the diagnosis of anaphylaxis, proposed by the WAO Anaphylaxis
544
Committee, 2019(64)
Anaphylaxis is highly likely when any one of the following 2 criteria are fulfilled: 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g. generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING: a. Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) b. Reduced BP or associated symptoms of end-organ dysfunction (e.g. hypotonia [collapse], syncope, incontinence) c. Severe gastrointestinal symptoms (e.g. severe crampy abdominal pain, repetitive vomiting), especially after exposure to non-food allergens 2. Acute onset of hypotension* or bronchospasm or laryngeal involvement# after exposure to a known or highly probable allergen for that patient (minutes to several hours§), even in the absence of typical skin involvement. PEF, Peak expiratory flow; BP, blood pressure. *Hypotension defined as a decrease in systolic BP greater than 30% from that person’s baseline, OR i.
Infants and children under 10 years: systolic BP less than (70mmHg + [2 x age in years])
ii.
Adults: systolic BP less than <90 mmHg
#
Laryngeal symptoms include: stridor, vocal changes, odynophagia.
§
The majority of allergic reactions occur within 1-2 hours of exposure, and usually much quicker.
Reactions may be delayed for some food allergens (e.g. alpha-gal) or in the context of immunotherapy, occurring up to 10 hours after ingestion.” 545
28 546
FIGURE LEGENDS
547 548
FIG 1: Time trends in hospital admissions (A) and fatalities (B) for all-cause anaphylaxis. Data from
549
Motosue et al (5) includes all patients admitted to either an observation unit or hospital ward. UK data
550
relating to admissions after 2012 is previously unpublished but is obtained using identical methodology
551
to that prior to 2012 (10).
552 553
FIG 2: Time trends in hospital admissions (A, adults and children; B, children only) and fatalities (C) for
554
food-induced anaphylaxis. Data from Motosue et al(6) includes all patients admitted to either an
555
observation unit or hospital ward. UK data relating to admissions after 2012 is previously unpublished
556
but is obtained using identical methodology to that prior to 2012 (10).
557 558
FIG 3: Time trends in hospital admissions (A) and fatalities (B) for anaphylaxis due to non-food triggers,
559
by agent (venom, medication and “unspecified”). Data from Motosue et al(6) includes all patients
560
admitted to either an observation unit or hospital ward.
561 562
FIG 4: Incidence of fatal anaphylaxis expressed as a proportion of hospital admissions, for all cause (A)
563
and due to food (B). Data for USA relating to case fatality rate for food anaphylaxis estimated using data
564
from Motosue et al(6) and Jerschow 2014 (20).
565
ALL CAUSE Australia7
20
Denmark2 Spain9
15
Taiwan11 UK (England)10
10
USA4 5
USA5
0 1995
2000
2005
2010
2015
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
ALL CAUSE 25
0.20
Australia3,8 Canada (Ontario)22
0.15
Finland21 0.10
France23 USA4
0.05
UK10
0.00 1995
2000
2005
2010
FOOD Australia3,8
15
Spain9 UK (England)10
10
USA5,6
5
0 1995
2000
2005
2010
2015
Hospital admissions per 100,000 population
FOOD (children only) Australia7 Finland19 Hong Kong17 Italy16 UK (England)10
10
5
USA18 USA15
0 1995
2000
2005
2010
2015
0.03
Australia3,8 Canada (Ontario)22
0.02
UK10 USA20
0.01
0.00 1995
20
15
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
FOOD 20
2000
2005
2010
VENOM
8 6
UK (England & Wales)10 USA5,6
4 2 0 1995
2000
2005
2010
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
VENOM 0.10
Australia3,8 Canada (Ontario)22 France23 UK10
0.05
USA20
0.00 1995
2015
Spain9 6
UK (England)10 USA5,6
4 2 0 2005
2010
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
Australia3
8
2000
Australia3,8 Canada (Ontario)22
UK10 USA20 0.00 1995
UK (England & Wales)10 USA5,6
2 0 2005
2010
2015
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
Spain9
4
2000
2005
2010
CAUSE UNSPECIFIED Australia3
6
France23
0.05
2015
8
2000
2010
0.10
CAUSE UNSPECIFIED
1995
2005
DRUG
DRUG
1995
2000
0.10
Australia3,8 Canada (Ontario)22 France23 USA20
0.05
0.00 1995
2000
2005
2010
% anaphylaxis admissions with a fatal outcome
CASE FATALITY: ALL CAUSE
1.5
Australia (all cause)3,8 UK (all cause)10
1.0
USA (all cause)20 0.5
0.0 2000
2005
2010
% anaphylaxis admissions with a fatal outcome
CASE FATALITY: FOOD Australia (all cause)3,8 1.5
Australia (food only)3,8
1.0
UK10 UK (food only)10
0.5
USA (all cause)20 USA (food only, estimated)6
0.0 2000
2005
2010
S2213-2198(19)30967-5
DOI:
https://doi.org/10.1016/j.jaip.2019.11.027
Reference:
JAIP 2571
To appear in:
The Journal of Allergy and Clinical Immunology: In Practice
Received Date: 4 October 2019 Revised Date:
18 November 2019
Accepted Date: 18 November 2019
Please cite this article as: Turner PJ, Campbell DE, Motosue MS, Campbell RL, Global Trends in Anaphylaxis Epidemiology and Clinical Implications, The Journal of Allergy and Clinical Immunology: In Practice (2019), doi: https://doi.org/10.1016/j.jaip.2019.11.027. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
1 1
Global Trends in Anaphylaxis Epidemiology and Clinical Implications
2 3
Paul J Turner FRACP PhD,1,2 Dianne E Campbell FRACP PhD,2,3 Megan S. Motosue, MD,4 Ronna L.
4
Campbell, M.D., Ph.D.5
5 6
1Section
of Inflammation, Repair & Development, National Heart & Lung Institute, Imperial College
7
London, London, United Kingdom; 2Discipline of Child and Adolescent Health, University of Sydney,
8
Sydney, Australia; 3Department of Allergy and Immunology, Children’s Hospital at Westmead,
9
Sydney, Australia; 4Department of Allergy and Immunology, University of Hawaii, John A. Burns
10
School of Medicine, Honolulu, Hawaii, United States; 5Department of Emergency Medicine, Mayo
11
Clinic College of Medicine and Science, Rochester, MN, United States
12 13
Corresponding author:
14
Ronna L. Campbell, MD, PhD
15
Department of Emergency Medicine, Mayo Clinic College of Medicine and Science
16
200 First St SW, Rochester, MN 55905
17
Tel: (507) 255-7002
18
Fax: 507-255-6592
19
Email: [email protected]
20 21
Author declaration: All authors have revised and approved the final version of the manuscript for
22
submission. This work is original and hasn’t been published nor is under consideration for
23
publication elsewhere.
2 24
Conflicts of interest: R.L. Campbell has received consulting fees from EB Medicine and is an author
25
for UpToDate. P.J. Turner reports grants from the UK Medical Research Council and National
26
Institute for Health Research (NIHR) Policy Research Programme; and received consultancy and
27
lecture fees from Aimmune Therapeutics, Allergenis and DBV Technologies. D.E Campbell receives
28
part time salary from DBV-technologies and reports grants from The National Health and Medical
29
Research Council of Australia (NHMRC), and received advisory board fees from Allergenis. M.S.
30
Motosue declares no conflicts of interest.
31
Funding Some of the data analysis in this manuscript was funded through a UK Medical Research
32
Council Clinician Scientist award to P.J. Turner (reference MR/K010468/1).
33
Word count: 2889
34
3 35
Abstract
36
The true global scale of anaphylaxis remains elusive, because many episodes occur in the
37
community without presentation to healthcare facilities, and most regions have not yet developed
38
reliable systems with which to monitor severe allergic events. The most robust datasets currently
39
available are based largely on hospital admissions, which are limited by inherent issues of
40
misdiagnosis, misclassification and generalizability. Despite this, there is convincing evidence of a
41
global increase in rates of all cause-anaphylaxis, driven largely by medication and food-related
42
anaphylaxis. There is no evidence of parallel increases in global all-cause anaphylaxis mortality,
43
with surprisingly similar estimates for case fatality rates at approximately 0.5-1% rate of fatal
44
outcomes for hospitalizations due to anaphylaxis across several regions.
45
Studying regional patterns of anaphylaxis to certain triggers have provided valuable insights into
46
susceptibility and sensitizing events: for example, the link between the monoclonal antibody
47
cetuximab and allergy to mammalian meat. Likewise, data from published fatality registers can
48
identify potentially modifiable risk factors which can be used to inform clinical practice, such as
49
prevention of delayed epinephrine administration, correct posturing during anaphylaxis, special
50
attention to populations at risk (such as the elderly on multiple medications) and use of venom
51
immunotherapy in individuals at risk of insect-related anaphylaxis.
4 52
Key words: Anaphylaxis, biphasic, epidemiology, time trends, food allergy.
5 53
Abbreviations
54
Ab, antibodies
55
CCL2, chemokine ligand-2
56
EAACI, European Academy of Allergy and Clinical Immunology
57
FAAN, Food Allergy and Anaphylaxis Network
58
ICD-11, International Classification of Disease, Eleventh Revision
59
ICU, Intensive Care Unit
60
LTP, Lipid Transfer Protein
61
NIAID, National Institute of Allergy and Infectious Diseases
62
UK, United Kingdom
63
USA, United States of America
64
WAO, World Allergy Organization
65
WHO, World Health Organization
66
α- gal, galactosyl-α-(1,3)-galactose
6 67
Introduction
68
Anaphylaxis represents the more severe end of the spectrum of allergic reactions, and is most
69
commonly triggered by medication, food or insect stings. Measuring and evaluating
70
epidemiological data related to episodes of anaphylaxis is an important means by which trends,
71
burden of disease and risk factors can be identified. Such information can highlight novel emerging
72
allergens, changes in epidemiology and risk-factor associations, which can in turn inform clinical
73
practice and may prevent future severe reactions and fatalities.
74
Difficulties in the collection and interpretation of epidemiological anaphylaxis data must be
75
acknowledged. These include variation in definitions of anaphylaxis across different regions of the
76
world, logistical and coding issues related to collection of large health service data sets and the
77
inherent difficulties in collecting data for a disease state which largely occurs in the community, not
78
within a hospital or health facility.
79 80
Trends in Anaphylaxis Epidemiology
81
Hospital admissions datasets represent the largest and most robust data available to understand
82
trends in anaphylaxis; however, they probably underestimate the true rate of anaphylaxis, as this
83
frequently occurs in the community or outside of hospital settings, and only the minority of cases
84
result in hospitalization.
85
Anaphylaxis accounts for up to 0.26% of overall hospital admissions(1). In general, the literature
86
reports global (UK, Europe, USA, Australia, New Zealand) increases in hospitalizations for
87
anaphylaxis – both with respect to all-cause anaphylaxis (Figure 1) and by trigger (Figures 2 &
88
3)(2-10); Taiwan appears to be an exception, where hospitalizations have not increased despite an
89
increase in hospital referrals for anaphylaxis(11). Data is available relating to hospital presentations
7 90
(rather than hospital admissions) from South Korea and New Zealand: all-cause anaphylaxis is
91
estimated to have increased 1.7-fold over the period 2010-2014 in South Korea(12), most markedly
92
in young children, while there has been a 2.8 fold increase in food-related anaphylaxis admissions
93
in children in New Zealand between 2006-2015(13).
94
There are significant differences in global anaphylaxis admission rates, with the highest rates in
95
Australia and lower rates reported in Spain, Taiwan and USA. This may be due, in part, to different
96
thresholds for observation in hospital following a reaction, and whether this occurs in an
97
“observation unit,” which may or may not be coded as a hospital admission. Less than 20% of
98
emergency presentations with anaphylaxis are admitted (either to an observation unit or to
99
hospital ward) in the USA(6), which could explain (at least in part) the lower rate of hospitalization
100
in the USA (similarly, in Spain, most patients are discharged without hospitalization). This is in
101
contrast to countries such as the UK where national guidelines recommend hospitalization for
102
anaphylaxis, particularly in children at first presentation(14). In general, the increase in
103
hospitalizations is predominantly due to food-related anaphylaxis, particularly in children(3, 4, 7, 8,
104
10, 15-19), although data are limited for non-food allergens (Figure 32B). Interestingly, rates of
105
hospitalization are roughly equivalent in most regions (although highest in Australia), which
106
implies that perhaps the threshold for in-patient observation is not particularly different between
107
countries.
108
Despite this increase, there is little evidence that the overall rate of fatal outcomes has increased(8,
109
10, 20-23), with the mortality rate declining in many regions. Furthermore, mortality seems similar
110
in those regions where data is available, at around 0.5-1 fatality per million (population). The
111
notable exception is Australia, where all-cause fatal anaphylaxis rates increased by 6.2% per annum
112
from 1997 to 2013, predominantly due to food triggers(8). However, when these data are analyzed
8 113
by case fatality rate (proportion of cases admitted to hospital which result in a fatal outcome),
114
mortality has fallen, including with respect to food-related fatal anaphylaxis in Australia (Figure 4).
115 116
Trigger specific epidemiology
117
Food represents the most common trigger for anaphylaxis admissions to hospital, but not the most
118
common cause of anaphylaxis-related fatalities. Hospitalizations due to food-related anaphylaxis
119
peak in the pediatric age range, but contribute significantly to adult admissions, where typically
120
anaphylaxis admissions due to medication exceed those due to food by the 6th decade onwards.
121
Mortality from food-related anaphylaxis is consistently lower than other causes across all regions.
122
This is in agreement with the observation that while food-induced anaphylaxis is relatively
123
common, fatal outcomes are rare, with a reported incidence of 1.35–2.71 per million person-
124
years(24). Curiously, the USA appears to have a lower mortality rate for food-related anaphylaxis
125
(but not the proportion of hospital admissions resulting in fatal outcome i.e. case fatality rate)
126
compared to other regions, despite a higher mortality from all-cause anaphylaxis (both in terms of
127
deaths per unit population and case fatality rate) compared to Canada and UK. The reasons for this
128
are unclear, but may be due to miscoding: Ma et al reported that 75% anaphylaxis fatalities
129
recorded between 1999 and 2009 in the USA were coded as “trigger unspecified”(4).
130
Both the USA and Australia have reported significant increases in fatality rates due to drug-induced
131
anaphylaxis(8, 20) (Figure 3B), which may represent an increasing tendency towards
132
polypharmacy in an ageing population – although there is no evidence that this has affected the
133
case fatality rate (Figure 4). Analysis of data from a national adverse drug reporting system in
134
Vietnam over the period 2010-2016 found a significant increase in the rate of drug related
135
anaphylaxis, predominantly attributed to antibiotics(25). McCall et al recently analyzed time
136
trends in USA anaphylaxis-related hospitalizations in pregnant women between 2004 and 2014, to
9 137
assess whether drug-related anaphylaxis had increased as a result of an increase in deliveries by
138
cesarean section; reassuringly, the authors did not identify such an increase in this specific patient
139
cohort(26).
140
Insect related anaphylaxis rates appear to have remained relatively stable (or decreasing) over
141
many years, in comparison to medication and food. Although they represent a small proportion of
142
hospital anaphylaxis admissions, they are relatively over-represented in fatalities, underlying the
143
seriousness of insect allergy. Potentially modifiable factors highlighted by anaphylaxis registries
144
include delayed treatment due to rural location of incident, lack of preparedness for anaphylaxis
145
and lack of prior immunotherapy for venom allergy(8).
146 147
Novel and emerging allergens
148
Lipid Transfer Protein (LTP)-associated food anaphylaxis is reported to be the most common cause
149
of food anaphylaxis in adults in the Mediterranean region(27), with a north-to-south regional
150
gradient in prevalence(28). It is also the most common trigger for exercise-associated, food-related
151
anaphylaxis in this region(29). The epidemiology of this syndrome elsewhere is unclear: although
152
sporadic case reports of LTP-associated food anaphylaxis occur globally, it remains unclear exactly
153
why this appears to be a largely Mediterranean phenomena, and whether rates are truly
154
increasing(30).
155
Allergy and anaphylaxis to the oligosaccharide galactosyl-α-(1,3)-galactose (α-gal) is an emerging
156
cause of anaphylaxis in tick-endemic regions globally. It was the regional USA epidemiology of
157
anaphylaxis to cetuximab – concentrated in the southeastern USA states of Tennessee, Arkansas
158
and South Carolina with few anaphylaxis cases reported in Massachusetts and northern California –
159
which led to the understanding that this form of anaphylaxis was related to prior sensitization to α-
10 160
gal via tick bites(31). In the form of non-primate mammalian meat anaphylaxis, symptoms present
161
with an “atypical” delay in onset from exposure to anaphylaxis - typically 3-6 hours following
162
mammalian meat ingestion(32, 33) (although reactions up to 10 hours after exposure have been
163
reported). Cases have been reported in most regions, including Australia(34), Japan(35), USA(30),
164
South America, Africa(36) and Europe, but it is unclear if rates are increasing, with many historical
165
cases likely to have been unrecognized and undiagnosed(37).
166
Monoclonal antibodies (mAb) are exponentially used in clinical practice to treat a wide range of
167
diseases, and represent a novel therapeutic class that is increasingly associated with anaphylaxis, as
168
recently reviewed(38). Ironically, the agent most commonly reported to trigger anaphylaxis is the
169
anti-IgE mAb omalizumab(38), however systematic reporting and analysis of co-factors related to
170
mAb-related anaphylaxis (aside from cetuximab) are currently lacking.
171 172
Biphasic Anaphylaxis
173
Studies assessing the frequency of biphasic anaphylaxis have been undertaken worldwide(39). The
174
true incidence of biphasic anaphylaxis remains unclear, hindered by the use of differing definitions
175
of biphasic anaphylaxis. Studies evaluating the incidence of biphasic reactions have reported rates
176
ranging from almost 20%(40) to less than 1%(41). A meta-analysis of 27 studies, which included
177
4114 patients with anaphylaxis and 192 biphasic reactions, reported a biphasic reaction rate of
178
4.6% and a median time of onset of 11 (range 0.2–72) hours(39). Risk factors associated with the
179
development of a biphasic reaction have been difficult to identify. However, the data suggest that
180
increased severity of the initial reaction, (42, 43), a wide pulse pressure(39, 44) at presentation,
181
increased requirement for epinephrine to treat the initial reaction(44-47), and delayed
182
administration of epinephrine (44, 45, 48)may increase the risk. Two systematic reviews(49, 50)
183
failed to find evidence that corticosteroids reduce the risk of a biphasic reaction. Although, no fatal
11 184
reactions have been reported in contemporary studies evaluating biphasic anaphylaxis,
185
approximately 20-55% of biphasic reactions are treated with epinephrine (40, 44, 46, 48, 51). In
186
addition, ICU admission may be required in 4-14% of patients (51, 52).
187 188
Collecting and interpreting anaphylaxis data - pitfalls and limitations
189
In order to effectively understand and learn from anaphylaxis data, it is important to understand
190
the potential biases that can confound any inferences made. Selection bias occurs when
191
anaphylaxis cases in any given dataset differ systematically from general anaphylaxis, resulting in
192
systematic differences which can impact interpretation. For example, there are a number of
193
different datasets which can be used to monitor epidemiological trends, ranging from emergency
194
department presentations to public datasets, health insurance databases and anaphylaxis registries.
195
These datasets may only capture cases presenting to specific healthcare facilities and not
196
anaphylaxis in the community, which often does not present to healthcare professionals. Insurance
197
databases may only include cases in insured individuals or those who present to specific facilities,
198
and are therefore unlikely to represent all socioeconomic groups. Anaphylaxis registries are, by
199
nature, retrospective and subject to reporting and recall bias, although one state in Australia now
200
has mandatory anaphylaxis reporting of any case presenting to a hospital facility (but not to
201
healthcare professionals outside hospital)(53).
202
Selection bias becomes a major confounder when evaluating severity: mild reactions may not be
203
included due to non-presentation to healthcare facilities, while severe (fatal) cases may occur pre-
204
hospital and not be registered, or misclassified as being due to a different cause of death. There is
205
little consensus as to what constitutes severe reactions: in a large prospective cohort of anaphylaxis
206
presenting to an emergency department, 31% of cases had wheeze without any other major organ
207
features (54). Such presentations might be coded as asthma rather than anaphylaxis. In contrast,
12 208
non-anaphylaxis reactions that involve significant generalized urticaria and facial angioedema
209
alone might be miscoded as anaphylaxis due to ‘visual’ severity. A further concern, particularly with
210
respect to drug-induced anaphylaxis, is under-recognition and under-reporting potentially due to
211
medicolegal concerns: many such cases result from patients being administered medication to
212
which they were already known to be allergic(8, 55).
213
The other important bias to consider is information bias, which relates to misclassification of data.
214
At a broad level, large datasets depend on medical coding, which are prone to misclassification(24,
215
56). This issue is further confounded by differences in the definition of anaphylaxis(14), and the
216
extent to which any definition is used to determine the coding, as recently highlighted by Wang et
217
al(57). It is not uncommon, particular in the emergency setting, for mild allergic reactions to be
218
coded as anaphylaxis, and vice versa(58,59). For example, 48% of anaphylactic reactions in an
219
emergency department in New York State were not coded as anaphylaxis despite fulfilling
220
diagnostic criteria (59). It is also possible that non-allergic anaphylaxis mimics such as chronic
221
idiopathic urticaria and hereditary angioedema could be misclassified as anaphylaxis. This can
222
impact interpretation, for example the inclusion of more mild cases as anaphylaxis will skew the
223
result of any intervention towards a more favorable outcomes (potential channeling bias).
224
Identifying specific anaphylaxis triggers is important, however this information is frequently not
225
collected with existing coding systems. Many coded anaphylaxis reactions are labelled “trigger
226
unspecified”, which hampers the evaluation of risk factors for severe reactions and in assessing
227
trends for specific triggers. For example, in an analysis of USA data between 1999 and 2009, over
228
two thirds of cases – hospitalizations and fatalities – were classified as “unspecified trigger”(4). The
229
new ICD-11 coding(60) should improve this, although there may be initial difficulties in monitoring
230
historical trends if different coding systems have to be integrated for analysis.
13 231
Caution is needed when interpreting mortality data: death certification is prone to miscoding (e.g.
232
cases of anaphylaxis may be miscoded as “severe asthma”)(61). Most death certification follows
233
WHO guidelines, where one part gives the condition or sequence of conditions leading directly to
234
death, a second section gives details of any associated conditions that contributed to the death, but
235
are not part of the causal sequence. There have been examples of this resulting in gross over-
236
estimates in terms of fatalities due to allergy, if death certificates include allergy diagnoses even
237
when they are not factors which contributed to the fatal outcome.
238
Monitoring the rate of hospital admissions is a frequent method used to assess epidemiology, but
239
there are many factors which determine whether a particular patient is admitted to hospital or
240
discharged. For example, guidance in the UK implemented in 2011 recommended that all children
241
with food-related allergic reactions be admitted to the hospital following presentation to the
242
emergency department, which might have caused an artefactual increase in rates of
243
hospitalization(10). Using prescription data for epinephrine auto-injectors as a surrogate for
244
prevalence is also subject to similar external “modifiers”, since changes in prescription patterns
245
cannot solely be attributed to changes in prevalence.
246
Despite limitations, analyzing changes in anaphylaxis epidemiology over time is an important tool
247
for clinicians, researchers and those advocating for improvements in health policy to address the
248
burden of disease. The effect of bias can be mitigated in part by the use of the same methodology to
249
compare trends in any given dataset – so although there may be issues relating to information bias,
250
if these are constant over the time period under study in any given dataset, then underlying trends
251
are likely to be real even if the biases confound any comparison between different datasets.
252 253
Lessons for Improvement in Diagnosis and Management
14 254
Recognition of anaphylaxis can be difficult: this is confounded by differences in diagnostic criteria.
255
This is particularly true for food-induced anaphylaxis: according to the National Institute of Allergy
256
and Infectious Diseases/ Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria(62)
257
(subsequently adopted by the World Allergy Organization (WAO)(63)), a food-induced reaction
258
with hives and vomiting could be consistent with anaphylaxis, but such a reaction (i.e. skin and gut
259
symptoms) would not be considered as anaphylaxis in the UK(64) and Australia(65), in the
260
absence of respiratory or cardiovascular symptoms. Furthermore, isolated respiratory reactions in
261
the absence of skin or gut symptoms are not classified as anaphylaxis according to NIAID/FAAN
262
criteria, despite this being a common presentation for fatal food anaphylaxis (66,67). For example,
263
in the largest phase 3 study of oral immunotherapy performed to date (the PALISADE study), at
264
least one third of 551 participants received epinephrine during entry food challenge (68), but only
265
28 had reactions which met the NIAID/FAAN criteria for anaphylaxis (69). Interestingly, 35
266
subjects were treated for wheezing – 7 more than those diagnosed with anaphylaxis – and at least
267
14 without anaphylaxis received multiple doses of epinephrine (69). These differences not only
268
impact patient care practices, but also have implications for service evaluation and research by
269
confounding comparisons of reported incidence rates of anaphylaxis and epinephrine use due to
270
differences in definition. Increased collaboration to create an international consensus is needed, to
271
avoid these incongruities. The WAO Anaphylaxis Committee has recently proposed a refinement of
272
the NIAID/FAAN criteria and its rationale for doing so(70) (Table 1), to help achieve this important
273
goal. Similarly, the implementation of ICD-11 classification will also improve consistency of coding
274
and facilitate future evaluation of epidemiological trends.
275
While largely a clinical diagnosis, biomarkers and specifically serum tryptase may support
276
the diagnosis of anaphylaxis and aid in differentiating anaphylaxis from its mimics such as
277
idiopathic systemic capillary leak syndrome and severe asthma, although serum tryptase is also
278
elevated in fatal asthma(71). This can be important in the context of monitoring trends for more
15 279
severe reactions. Yet despite its recommendation in current guidelines(63, 72), the role of tryptase
280
in “real world” practice remains debated. From a practical standpoint, serum tryptase is not readily
281
available to emergency providers as it often takes several days for results to become available.
282
Moreover, while the positive predictive value of serum tryptase is high (93%), the negative
283
predictive value is low (17%) (73) and may not be helpful, particularly for food-induced
284
anaphylaxis when tryptase is frequently not elevated. Other biomarkers (such as platelet-activating
285
factor, cysteinyl leukotrienes, chemokine ligand-2 (CCL2)) have been proposed(74) but can be
286
difficult to measure even under laboratory conditions. Future studies may need to consider
287
examining the sensitivity and specificity of a combination of biomarkers.
288
With regards to anaphylaxis management , while epinephrine remains the first line
289
treatment, glucocorticoids and antihistamines including both H1- and H2-antihistamines are often
290
recommended as second-line treatment (although the latest European Academy of Allergy and
291
Clinical Immunology (EAACI) guidelines relegate antihistamines to a 3rd line measure to help
292
relieve cutaneous symptoms, due to concerns that their use might delay the appropriate further
293
administration of epinephrine or fluids during patient stabilization)(75). The benefit of
294
antihistamines and glucocorticoids in both acute management and prevention of biphasic reactions
295
has not been established, and there is increasing evidence that glucocorticoids may be harmful
296
rather than simply being of no benefit(76). What role, if any, glucocorticoids and antihistamines
297
should have in anaphylaxis management needs further clarification, potentially through
298
comparison of outcomes between different units/regions. Reports from regional fatal anaphylaxis
299
registries have suggested that modifiable risk factors for severe and fatal anaphylaxis appear to
300
include polypharmacy in the elderly, delayed administration of epinephrine, maintaining an upright
301
posture (with dependent lower body) during anaphylaxis, failure to recognized past history of
302
medication allergies and failure to undertake venom immunotherapy in at-risk venom-allergic
303
individuals (77).
16 304
Comprehensive management of patients who have had anaphylaxis can be complex, so
305
partnerships between allergy specialists, emergency medicine and primary care providers are
306
necessary. Exploring the use of new tools, including the use of electronic medical records in
307
providing structured ordered sets, discharge instructions and automatic allergy referral system,
308
may provide additional solutions to improve the diagnosis and management of anaphylaxis.
309
17 310
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311
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Table 1: Amended criteria for the diagnosis of anaphylaxis, proposed by the WAO Anaphylaxis
544
Committee, 2019(64)
Anaphylaxis is highly likely when any one of the following 2 criteria are fulfilled: 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g. generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING: a. Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) b. Reduced BP or associated symptoms of end-organ dysfunction (e.g. hypotonia [collapse], syncope, incontinence) c. Severe gastrointestinal symptoms (e.g. severe crampy abdominal pain, repetitive vomiting), especially after exposure to non-food allergens 2. Acute onset of hypotension* or bronchospasm or laryngeal involvement# after exposure to a known or highly probable allergen for that patient (minutes to several hours§), even in the absence of typical skin involvement. PEF, Peak expiratory flow; BP, blood pressure. *Hypotension defined as a decrease in systolic BP greater than 30% from that person’s baseline, OR i.
Infants and children under 10 years: systolic BP less than (70mmHg + [2 x age in years])
ii.
Adults: systolic BP less than <90 mmHg
#
Laryngeal symptoms include: stridor, vocal changes, odynophagia.
§
The majority of allergic reactions occur within 1-2 hours of exposure, and usually much quicker.
Reactions may be delayed for some food allergens (e.g. alpha-gal) or in the context of immunotherapy, occurring up to 10 hours after ingestion.” 545
28 546
FIGURE LEGENDS
547 548
FIG 1: Time trends in hospital admissions (A) and fatalities (B) for all-cause anaphylaxis. Data from
549
Motosue et al (5) includes all patients admitted to either an observation unit or hospital ward. UK data
550
relating to admissions after 2012 is previously unpublished but is obtained using identical methodology
551
to that prior to 2012 (10).
552 553
FIG 2: Time trends in hospital admissions (A, adults and children; B, children only) and fatalities (C) for
554
food-induced anaphylaxis. Data from Motosue et al(6) includes all patients admitted to either an
555
observation unit or hospital ward. UK data relating to admissions after 2012 is previously unpublished
556
but is obtained using identical methodology to that prior to 2012 (10).
557 558
FIG 3: Time trends in hospital admissions (A) and fatalities (B) for anaphylaxis due to non-food triggers,
559
by agent (venom, medication and “unspecified”). Data from Motosue et al(6) includes all patients
560
admitted to either an observation unit or hospital ward.
561 562
FIG 4: Incidence of fatal anaphylaxis expressed as a proportion of hospital admissions, for all cause (A)
563
and due to food (B). Data for USA relating to case fatality rate for food anaphylaxis estimated using data
564
from Motosue et al(6) and Jerschow 2014 (20).
565
ALL CAUSE Australia7
20
Denmark2 Spain9
15
Taiwan11 UK (England)10
10
USA4 5
USA5
0 1995
2000
2005
2010
2015
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
ALL CAUSE 25
0.20
Australia3,8 Canada (Ontario)22
0.15
Finland21 0.10
France23 USA4
0.05
UK10
0.00 1995
2000
2005
2010
FOOD Australia3,8
15
Spain9 UK (England)10
10
USA5,6
5
0 1995
2000
2005
2010
2015
Hospital admissions per 100,000 population
FOOD (children only) Australia7 Finland19 Hong Kong17 Italy16 UK (England)10
10
5
USA18 USA15
0 1995
2000
2005
2010
2015
0.03
Australia3,8 Canada (Ontario)22
0.02
UK10 USA20
0.01
0.00 1995
20
15
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
FOOD 20
2000
2005
2010
VENOM
8 6
UK (England & Wales)10 USA5,6
4 2 0 1995
2000
2005
2010
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
VENOM 0.10
Australia3,8 Canada (Ontario)22 France23 UK10
0.05
USA20
0.00 1995
2015
Spain9 6
UK (England)10 USA5,6
4 2 0 2005
2010
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
Australia3
8
2000
Australia3,8 Canada (Ontario)22
UK10 USA20 0.00 1995
UK (England & Wales)10 USA5,6
2 0 2005
2010
2015
Fatalities due to anaphylaxis per 100,000 population
Hospital admissions per 100,000 population
Spain9
4
2000
2005
2010
CAUSE UNSPECIFIED Australia3
6
France23
0.05
2015
8
2000
2010
0.10
CAUSE UNSPECIFIED
1995
2005
DRUG
DRUG
1995
2000
0.10
Australia3,8 Canada (Ontario)22 France23 USA20
0.05
0.00 1995
2000
2005
2010
% anaphylaxis admissions with a fatal outcome
CASE FATALITY: ALL CAUSE
1.5
Australia (all cause)3,8 UK (all cause)10
1.0
USA (all cause)20 0.5
0.0 2000
2005
2010
% anaphylaxis admissions with a fatal outcome
CASE FATALITY: FOOD Australia (all cause)3,8 1.5
Australia (food only)3,8
1.0
UK10 UK (food only)10
0.5
USA (all cause)20 USA (food only, estimated)6
0.0 2000
2005
2010